tbuckley/cabot-search huggingface dataset:
Establishment of a novel BRCAness score that predicts response to PARP inhibitors.
Authors: Masanori Oshi, Shipra Gandhi, Rongrong Wu, Mariko Asaoka, Li Yan, Akimitsu Yamada, Kazutaka Narui, Shinya Yamamoto, Takashi Ishikawa, Itaru Endo, Kazuaki Takabe
Journal: Journal of Clinical Oncology (2022)

549 Background: BRCAness is a generic term used to describe characteristic features of homologous recombination deficiency (HRD) mimicking mutations in BRCA genes. Although clinical genetic testing has increased the detection of mutations in BRCA1 and BRCA2, we hypothesized that a measure to quantify BRCAness will identify the responders to PARP inhibitors that cause synthetic lethality in BRCA mutation tumors. Methods: The BRCAness score was established by using gene set variation analysis (GSVA) algorithm on 34 BRCA-mutation related genes. We investigated the clinical relevance of the score by performing silico analyses of 6245 breast cancer patients using multiple independent large cohorts in this study. Results: A score to quantify BRCAness was generated using gene set variation analysis algorithm on 34 BRCA1-mutation related genes selected by high AUC levels in ROC curve between BRCA1 mutation and wildtype breast cancer. The score was significantly associated with BRCA1 mutation, high overall mutation load and intratumoral heterogeneity as well as high HRD, DNA repair and MKI67 expression regardless of mutation in BRCA gene. High score tumor enriched not only DNA repair, but also five cell proliferation-related gene sets (E2F targets, G2M checkpoint, MYC targets v1 and v2, and MITOTIC signaling) in Hallmark collection (all false discovery rate &lt; 0.10). Breast cancers with high score were significantly associated with higher infiltration of anti-cancerous immune cells and higher cytolytic activity. Not all breast cancer cell lines with BRCA-mutation showed high score and the other cells in human breast cancer tumor microenvironment were contributing to the score. We found that the BRCAness score was the highest in triple-negative among subtypes consistently in all cohorts (all p &lt; 0.001). Finally, BRCAness was associated with response to chemotherapy and correlated strongly with response to PARP inhibitor in both triple-negative (AUC = 0.815) and ER-positive/HER2-negative breast cancer (AUC = 0.715). Conclusions: We established a novel BRCAness score using mRNA expression of BRCA-mutation-related genes and found that it associates with DNA repair and response to PARP inhibitor regardless of BRCA mutation.
Population dynamics and genetic connectivity in recent chimpanzee history
Authors: Claudia Fontsere, Martin Kuhlwilm, Carlos Morcillo-Suarez, Marina Alvarez-Estape, Jack D. Lester, Paolo Gratton, Joshua M. Schmidt, Paula Dieguez, Thierry Aebischer, Paula Álvarez-Varona, Anthony Agbor, Samuel Angedakin, Alfred K. Assumang, Emmanuel A. Ayimisin, Emma Bailey, Donatienne Barubiyo, Mattia Bessone, Andrea Carretero-Alonso, Rebecca Chancellor, Heather Cohen, Emmanuel Danquah, Tobias Deschner, Andrew Dunn, Jef Dupain, Villard E. Egbe, Olga Feliu, Annemarie Goedmakers, Anne-Céline Granjon, Josephine Head, Daniela Hedwig, Veerle Hermans, R. Adriana Hernandez-Aguilar, Inaoyom Imong, Sorrel Jones, Jessica Junker, Parag Kadam, Mike Kaiser, Mbangi Kambere, Magloire V. Kambale, Ammie K. Kalan, Ivonne Kienast, Deo Kujirakwinja, Kevin Langergraber, Juan Lapuente, Bradley Larson, Anne Laudisoit, Kevin Lee, Manuel Llana, Miquel Llorente, Sergio Marrocoli, David Morgan, Felix Mulindahabi, Mizuki Murai, Emily Neil, Sonia Nicholl, Stuart Nixon, Emma Normand, Chris Orbell, Lucy J. Ormsby, Liliana Pacheco, Alex Piel, Laura Riera, Martha M. Robbins, Aaron Rundus, Crickette Sanz, Lilah Sciaky, Volker Sommer, Fiona A. Stewart, Nikki Tagg, Luc Roscelin Tédonzong, Els Ton, Joost van Schijndel, Virginie Vergnes, Erin G. Wessling, Jacob Willie, Roman M. Wittig, Yisa G. Yuh, Kyle Yurkiw, Klaus Zuberbuehler, Jochen Hecht, Linda Vigilant, Christophe Boesch, Aida M. Andrés, David A. Hughes, Hjalmar S. Kühl, Esther Lizano, Mimi Arandjelovic, Tomas Marques-Bonet
Journal: Cell Genomics (2022)

Knowledge on the population history of endangered species is critical for conservation, but whole-genome data on chimpanzees (Pan troglodytes) is geographically sparse. Here, we produced the first non-invasive geolocalized catalog of genomic diversity by capturing chromosome 21 from 828 non-invasive samples collected at 48 sampling sites across Africa. The four recognized subspecies show clear genetic differentiation correlating with known barriers, while previously undescribed genetic exchange suggests that these have been permeable on a local scale. We obtained a detailed reconstruction of population stratification and fine-scale patterns of isolation, migration, and connectivity, including a comprehensive picture of admixture with bonobos (Pan paniscus). Unlike humans, chimpanzees did not experience extended episodes of long-distance migrations, which might have limited cultural transmission. Finally, based on local rare variation, we implement a fine-grained geolocalization approach demonstrating improved precision in determining the origin of confiscated chimpanzees.
QOPI Clinical Informatics: A digital platform to enable real-time quality reporting, clinical decision support, and rapid learning.
Authors: Casey B. Williams, Kubra Karagoz, Rachel Elsey, Tobias Meißner, Mitchell Higashi, Eric Schadt, Tomi Jun, Xiaoyan Wang, Rong Chen, Xiang Zhou, Sunny Guin, John H. Lee, William K. Oh
Journal: Journal of Clinical Oncology (2022)

e13545 Background: The ASCO Quality Oncology Practice Initiative (QOPI) was established in 2006 to facilitate quality measurement and continuous improvement of cancer care. 1 ASCO and QOPI leadership encourage a continuous learning environment to develop new tools and methodologies that improve quality and maximize outcomes and value in oncology practice. 2 Parallel advances in tumor molecular profiling, bioinformatics, and EMR data curation are adding new insights to support the real-world research of longitudinal patient journeys. Methods: Referencing the QOPI Certification Track 2021 Measures Summary, we employed data visualization techniques to create a precision oncology dashboard for breast cancer. This evaluation included 409 breast cancer patients for whom genomic testing was performed and presented at the Avera molecular tumor board. Patients were then matched to appropriate biomarker-based targeted therapies. Results: The dashboard identified and prioritized areas for enhanced data capture to inform strategies for care-coordination, research, and delivery of specialized care. Conclusions: An interactive, visual platform may help facilitate the integration of QOPI reporting into CancerLinQ, thereby fostering a real-time, bidirectional system for quality reporting, clinical decision support, and rapid learning. 3,4 The next stage will (1) expand the tumor list; and (2) apply NLP methods to assess accuracy, outcomes and temporal reasoning to create interactive graphs for patient referral patterns and surgery decision drivers. References: 1. Neuss MN, Desch CE, McNiff KK, et al: A process for measuring the quality of cancer care: The Quality Oncology Practice Initiative. J Clin Oncol. 2005 2. Blayney DW, McNiff K, Eisenberg PD, Gilmore T, Jacobsen PB, Jacobson JO, Kadlubek PJ, Neuss MN, Simone J. Development and future of the American Society of Clinical Oncology's Quality Oncology Practice Initiative. J Clin Oncol. 2014 3. Blayney DW: Enhancing quality through innovation: American Society of Clinical Oncology presidential address 2010. J Clin Oncol. 2010 4. Schilsky R, Hauser R, Mann J, et al: Lessons learned from the development of the CancerLinQ prototype: Clinical decision support. J Clin Oncol. 31, 2013[Table: see text]
Expanding clinical actionability in individual patient profiles with the Molecular Oncology Almanac.
Authors: Brendan Michael Reardon, Eliezer Mendel Van Allen
Journal: Journal of Clinical Oncology (2022)

3015 Background: The clinical care of oncology patients is routinely informed by tumor and inherited genetic profiles. This is accomplished by molecular pathologists synthesizing the growing body of clinical guidelines and scientific evidence that associates cancer genome alterations and therapeutic response, and applying that knowledge during case reviews. Many academic medical centers formalize this process in the form of molecular tumor boards. As the number of cases for review and literature continue to increase, there is opportunity to leverage clinical interpretation algorithms to computationally prioritize molecular features and both enhance and automate the sample contextualization process. Here, we present the Molecular Oncology Almanac (MOAlmanac) to enable the rapid assessment of tumor actionability. Methods: Molecular Oncology Almanac is an open source clinical interpretation algorithm and paired knowledge base for precision cancer medicine. It is used to rapidly characterize and identify genomic features related to therapeutic sensitivity and resistance and of prognostic relevance. This is performed by assessing not only individual genomic features (e.g. somatic variants, copy number alterations, germline variants, and fusions) but also interactions between these events as well as secondary features such as mutational burden, mutational signatures, MSI status, and aneuploidy. MOAlmanac summarizes all clinically relevant findings into a web-based actionability report. The underlying knowledge base can be accessed through our API endpoints and web browser, and entries may be recommended through either Github or our browser extension. In addition, we developed a cloud-based web portal on top of the Terra framework to increase accessibility. Results: A total of 32,108 samples from 30,607 patients across 66 cancer types received targeted sequencing to characterize somatic variants, copy number alterations, and fusions from PROFILE’s Oncopanel and were evaluated with MOAlmanac. Based on Oncopanel’s tier 1 and tier 2 criteria for clinical actionability, we observed that 8,285 samples (26%, 0 - 69% by cancer type) of patients harbored at least one alteration suggesting therapeutic sensitivity based on FDA approvals or clinical guidelines. Actionability increases to 18,117 samples (56%, 0 - 85% by cancer type) when considering an expanded set of evidence to include relationships captured from clinical trials, clinical, preclinical, and inferential evidence; consequently providing at least one therapeutic hypothesis to otherwise variant-negative patients. Conclusions: Clinical actionability of molecular tumor data was increased in individual patients by expanding the set of evidence considered. Source code and a web portal for this project are available at moalmanac.org .
Dose-dense neoadjuvant chemotherapy in triple-negative breast cancer: Real-world data from a developing country.
Authors: Rakesh Kumar Sharma, Ajay Gogia, Hari Krishna Raju Sagiraju, S V Suryanarayana Deo, Dayanand Sharma, Sandeep Mathur
Journal: Journal of Clinical Oncology (2022)

e12594 Background: Dose-dense adjuvant chemotherapy has been shown to be associated with improved long-term survival outcomes in triple-negative breast cancer (TNBC). However, there is a lacuna of data on the benefits of dose-dense neo-adjuvant chemotherapy (NACT) in TNBC particularly with respect to pathological complete response (pCR) rates and with the relapse or overall survival. To our knowledge no studies have been reported regarding the use or benefit of dose-dense NACT (ddNACT) over conventional NACT (cNACT) among Indian women with TNBC. Methods: This retrospective study included, 217 newly diagnosed cases of TNBC, treated with sequential anthracycline and taxane based NACT followed by definitive surgery. Study groups consisted of 137 patients who received 3-weekly conventional chemotherapy (cNACT group) and 80 patients with 2-weekly dose-dense NACT (ddNACT group) with granulocyte-colony-stimulating factor (GCSF) prophylaxis. Primary endpoint of the study was pathological complete response (pCR) rate and secondary endpoints were relapse-free survival (RFS), overall survival (OS) and grade-3/4 chemotoxicities. Fisher’s exact test was used to compare pCR rates. Kaplan-Meier and cox regression survival analysis were used to compare survival outcomes. Results: Median age (Interquartile range) in overall population, cNACT and ddNACT group were 43 (37-50), 44 (37-50) and 42 (36.5-48) years respectively. Baseline parameters were comparable between study groups, except that ddNACT group had higher proportion of premenopausal patients as compared to cNACT group (72.5% vs 55.5%). Majority of the patients presented at advanced stage, with stage-III being predominant, constituted by 97 (70.1%) and 55 (67.5%) patients in cNACT and ddNACT group respectively. No significant difference in pCR rate (32.8% vs 31.3%; p=0.808) was observed across the study groups. In multivariate analysis, dose-dense chemotherapy was no better than conventional chemotherapy for achieving pCR (Odds ratio [OR]: 0.86, 95% confidence interval [CI]: 0.45-1.63; p=0.639 and had no RFS advantage over conventional chemotherapy [Median RFS: Not reached in ddNACT vs 56.1 months in cNACT; Hazard Ratio: 0.83, 95% CI (0.48-1.44)]. OS was also comparable in both the groups with 3-year survival rate of 78.8% (95%CI: 60.9-89.2) in ddNACT group vs 84.3% (95% CI: 74.8-90.4) in cNACT group. Grade-3/4 toxicities were comparable in both groups. Conclusions: This observational study focusing on ddNACT among TNBC patients demonstrated similar pCR and toxicity rates with no significant survival benefits compared to cNACT regimen. Cost-benefits of frequent hospital visits for GCSF administration associated with dose dense therapy need further consideration before implementing such these regimens in lower-middle income countries.
Effect of durvalumab in patients with unresectable stage 3 non–small cell lung cancer post-chemoradiotherapy.
Authors: Aswani Thurlapati, Lovekirat Singh Dhaliwal, Sumasri Chennapragada, Pranavteja Gutta, Diana Song, Deepika Ralla, Jill Comeau, Runhua Shi, Kavitha Beedupalli
Journal: Journal of Clinical Oncology (2022)

8550 Background: The PACIFIC study (PS) concluded that the use of durvalumab from 1 to 42 days after concurrent chemoradiotherapy (CXRT) in stage 3 unresectable non-small cell lung cancer (NSCLC) increased the median overall survival (mOS) from 29 to 48 months. It also showed a benefit in tumors with PD-L1 &lt;25%. However, a post-hoc analysis of the PS showed no survival benefit with durvalumab in patients with PD-L1 &lt;1% but was not statistically powered. Currently in the US, durvalumab is approved irrespective of PDL-1 percentage, whereas in Europe it is not approved for tumors with PDL-1 &lt;1%. Also, there was no survival benefit in starting durvalumab within and after 2 weeks of CXRT. Our objectives in this study are to analyze the impact of PDL-1 expression and the date of initiation of durvalumab post CXRT on mOS. Methods: We conducted a retrospective observational study of stage 3 unresectable NSCLC patients who received durvalumab post CXRT at LSU Health Shreveport from 2018 to 2021. A survival analysis was done including the following variables: age, race, sex, tumor histology, tumor PD-L1 percentage, and date of initiation of durvalumab post CXRT. P-value &lt;0.05 was considered statistically significant. Results: We identified 83 patients who received durvalumab after CXRT for treatment of stage 3 unresectable NSCLC. Baseline characteristics are provided in table 1. Among all the tumors, 25% had a PDL-1 &lt;1%. 33% of the study population received durvalumab less than 30 days after CXRT and 67% received it after 30 days. The mOS was not impacted by race, sex, or tumor hisotology. Compared to higher PDL-1 percentage, patients with PD-L1 &lt;1% had a statistically significant lower survival probability. At 14 months, 87% of patients with a PD-L1 &lt;1% were alive compared to 100% in those with a PD-L1 1-50% or a PD-L1 &gt;50%. Less than 35% of patients with PD-L1 &lt;1% survived beyond 30 months compared to 45% for PD-L1 1-50% and 100% for PD-L1 &gt;50% (p-value 0.02). Patients who received durvalumab 30-60 days after concurrent CXRT had a lower OS at 30 months compared to those who started before 30 days (44% versus 90%). However, statistical significance was not reached (p-value 0.45). Conclusions: This study demonstrates that patients with a PD-L1 tumor expression of &lt;1% had a statistically significant lower survival probability compared to those with a PD-L1 expression of 1-50% and &gt; 50% in this patient population. Time from CXRT to the start of durvalumab was not shown to affect survival outcomes.[Table: see text]
Astrocyte-targeted gene delivery of interleukin 2 specifically increases brain-resident regulatory T cell numbers and protects against pathological neuroinflammation
Authors: Lidia Yshii, Emanuela Pasciuto, Pascal Bielefeld, Loriana Mascali, Pierre Lemaitre, Marika Marino, James Dooley, Lubna Kouser, Stijn Verschoren, Vasiliki Lagou, Hannelore Kemps, Pascal Gervois, Antina de Boer, Oliver T. Burton, Jérôme Wahis, Jens Verhaert, Samar H. K. Tareen, Carlos P. Roca, Kailash Singh, Carly E. Whyte, Axelle Kerstens, Zsuzsanna Callaerts-Vegh, Suresh Poovathingal, Teresa Prezzemolo, Keimpe Wierda, Amy Dashwood, Junhua Xie, Elien Van Wonterghem, Eline Creemers, Meryem Aloulou, Willy Gsell, Oihane Abiega, Sebastian Munck, Roosmarijn E. Vandenbroucke, Annelies Bronckaers, Robin Lemmens, Bart De Strooper, Ludo Van Den Bosch, Uwe Himmelreich, Carlos P. Fitzsimons, Matthew G. Holt, Adrian Liston
Journal: Nature Immunology (2022)

The ability of immune-modulating biologics to prevent and reverse pathology has transformed recent clinical practice. Full utility in the neuroinflammation space, however, requires identification of both effective targets for local immune modulation and a delivery system capable of crossing the blood-brain barrier. The recent identification and characterization of a small population of regulatory T (Treg) cells resident in the brain presents one such potential therapeutic target. Here, we identified brain interleukin 2 (IL-2) levels as a limiting factor for brain-resident Treg cells. We developed a gene-delivery approach for astrocytes, with a small-molecule on-switch to allow temporal control, and enhanced production in reactive astrocytes to spatially direct delivery to inflammatory sites. Mice with brain-specific IL-2 delivery were protected in traumatic brain injury, stroke and multiple sclerosis models, without impacting the peripheral immune system. These results validate brain-specific IL-2 gene delivery as effective protection against neuroinflammation, and provide a versatile platform for delivery of diverse biologics to neuroinflammatory patients.
Maintenance olaparib in patients (pts) with platinum-sensitive relapsed ovarian cancer (PSROC) by somatic (s) or germline (g) BRCA and other homologous recombination repair (HRR) gene mutation status: Overall survival (OS) results from the ORZORA study.
Authors: Sandro Pignata, Amit M. Oza, Geoff Hall, Beatriz Pardo, Radoslaw Madry, David Cibula, Jaroslav Klat, Ana Montes, Rosalind Glasspool, Nicoletta Colombo, Imre Pete, Ana Herrero, Marga Romeo, Rumyana Nedyalkova Ilieva, Constanta Timcheva, Massimo Di Maio, Alan Barnicle, Rosemary Taylor, Zahid Bashir, Andrew R. Clamp
Journal: Journal of Clinical Oncology (2022)

5519 Background: In the SOLO2 (NCT01874353) trial, maintenance olaparib provided clinically meaningful improvement in OS for PSROC pts with a gBRCA mutation (m) compared with placebo (median 51.7 vs 38.8 months [mo], respectively). The ORZORA trial (NCT02476968) assessed efficacy and safety of maintenance olaparib in PSROC pts with a BRCAm (s or g) or a non-BRCA HRRm. Median progression-free survival (18.0 mo, BRCAm; 16.4, non-BRCA HRRm) was reported at primary data cutoff (DCO). We report final OS analyses. Methods: We conducted an open-label, single-arm, multicenter study of PSROC pts in response to platinum-based chemotherapy (PBC) after ≥2 prior lines of PBC. Pts underwent prospective central screening for tumor BRCAm status (myChoice CDx, Myriad Genetic Laboratories, Inc.), then central gBRCAm testing (BRACAnalysis CDx, Myriad Genetic Laboratories, Inc.) to determine s or g status. An exploratory cohort comprised of pts with predefined non-BRCA HRRm (FoundationOne CDx, Foundation Medicine, Inc.). Pts received maintenance olaparib (400 mg bid; capsules) until progression. OS and time to second progression (PFS2) were secondary endpoints. Results: 181 pts were enrolled (BRCAm n = 145 [s, n = 55; g, n = 87; s/g status unknown, n = 3]; non-BRCA HRRm, n = 33; unassigned, n = 3). At DCO (June 25, 2021), median OS follow-up in censored pts was 42.6 mo in BRCAm and 39.3 mo in non-BRCA HRRm pts. OS and PFS2 are reported in the Table. PBC was received as a subsequent therapy by 33.1% BRCAm, 32.7% sBRCAm, 33.3% gBRCAm, and 45.5% non-BRCA HRRm pts. 177 pts received ≥1 dose of olaparib and were included in safety analyses; 6.2% of pts discontinued because of adverse events (AEs). 37.9% of pts reported grade ≥3 AEs, the most common being anemia (16.4%). Since primary DCO, one new primary malignancy and four myelodysplastic syndrome events occurred. Conclusions: In final OS analyses, maintenance olaparib capsules showed consistent clinical activity in BRCAm and sBRCAm PSROC pts. Exploratory analyses suggest similar activity in non-BRCA HRRm pts. No new safety signals were observed. Findings highlight that PSROC pts, beyond those with a gBRCAm, can benefit from maintenance olaparib. Clinical trial information: NCT02476968. [Table: see text]
Profile and survival outcomes among patients with second malignancies following a primary chronic myeloid leukemia: An analysis of the SEER database (1975-2016).
Authors: Oluwasegun Akinyemi, Faith Abodunrin, Kindha Elleissy Nasef, Bolarinwa Akinwumi, Irene Akinyemi, Ademola Ojo, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2022)

e19060 Background: A major concern of cancer survivors is the occurrence of a subsequent cancer. A small proportion of patients with CML develop second cancers. Little is known about these patients. In the present study, we determined the profile and determinants of survival among patients with a primary CML who developed subsequent malignancies. Methods: We utilized the SEER 18 Registry 1975-2016 to conduct a retrospective analysis of patients who developed a subsequent malignancy following a primary CML diagnosis. The outcome of interest was the latency interval between the initial primary CML diagnosis and a subsequent malignancy. Utilizing the cox regression model, we determined the factors associated with the overall survival after controlling for disease stage, treatment modalities, and social determinants of health. Results: There were 2, 312 CML Patients who developed a subsequent malignancy in the study period. Among these patients, 76.3% were non-Hispanic Whites, 9.6% were non-Hispanic Blacks, and 8.7% were Hispanics. 63.0% of the study population were males. The mean age at primary diagnosis of CML was 63.2 ± 15.6 yrs. While the mean age at diagnosis of the subsequent malignancy was 66.9 ± 14.5 yrs. The commonest subsequent malignancies were Acute Myeloid Leukemia (12.9%), Prostate cancers (12.7%), Lung and Bronchi cancers (11.5%), and Breast cancers (5.9%). The mean latency interval for developing a subsequent malignancy following a CML was 3.7± 4.4 years. Significant predictors of reduced survival include increasing age (HR = 1.02; 95% CI 1.01-1.03), Latency interval &lt; 5years (HR = 0.32; 95% CI 0.17-0.60) and Hispanic ethnicity (HR = 1.78; 95% CI 1.09-2.92). Conclusions: Common second malignancies following a primary diagnosis of CML include prostate cancers, lung and bronchi cancers, and breast malignancies. Major predictors of adverse outcomes include advanced age, development of second cancers within 5 years of primary CML diagnosis, and Hispanic ethnicity.